Field of the Disclosure
The present invention relates to procoagulant compounds useful for the treatment of bleeding diseases or disorders.
Background
The blood coagulation pathway, in part, involves the formation of an enzymatic complex of Factor VIIIa (FVIIIa) and Factor IXa (FIXa) (Xase complex) on the surface of platelets. FIXa is a serine protease with relatively weak catalytic activity without its cofactor FVIIIa. The Xase complex cleaves Factor X (FX) into Factor Xa (FXa), which in turn interacts with Factor Va (FVa) to cleave prothrombin and generate thrombin. Hemophilia A is a bleeding disorder caused by mutations and/or deletions in the factor VIII (FVIII) gene resulting in a deficiency of FVIII activity (Peyvandi et al. 2006). Hemophilia B (also known as Christmas disease) is one of the most common inherited bleeding disorders in the world. It results in decreased in vivo and in vitro blood clotting activity and requires extensive medical monitoring throughout the life of the affected individual.
Treatment of hemophilia is by replacement therapy targeting restoration of clotting activity. There are plasma-derived and recombinant clotting factor products available to treat bleeding episodes on-demand or to prevent bleeding episodes from occurring by treating prophylactically. Based on the half-life of these products, treatment regimens require frequent intravenous administration. Such frequent administration is painful and inconvenient. Strategies to extend the half-life of clotting factors include pegylation (Rostin J, et al., Bioconj. Chem. 2000; 11:387-96), glycopegylation (Stennicke H R, et al., Thromb. Haemost. 2008; 100:920-8), formulation with pegylated liposomes (Spira J. et al., Blood 2006; 108:3668-3673, Pan J, et al., Blood 2009; 114:2802-2811) and conjugation with albumin (Schulte S., Thromb. Res. 2008; 122 Suppl 4:S14-9). However, modification of coagulation factors and procoagulant peptides with half-life extending moieties (e.g., PEG) and other similar strategies to extend their half-lives can lead to compromised activity. In order to rescue their activity, a cleavable linker can be inserted between the protein or peptide of interest and its modifier. The chosen cleavable linker must be cleaved efficiently and rapidly by a protease, for example, a protease involved in the coagulation cascade. Thrombin being the activator of many clotting factors is the most popular choice. However, all known substrate sequences composed of natural amino acids (e.g., LVPR, ALRPR (SEQ ID NO: 7), etc.) are not optimal substrates. Furthermore, covalent binding of the cleavable linker to a coagulation factors or procoagulant peptide can result in steric hindrances (e.g., due to the presence of amino acids such as such as proline, isoleucine or arginine C-terminal to the cleavage site) that can prevent an efficient enzymatic cleavage reaction.